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SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis
- Source :
- Proceedings of the National Academy of Science of the United States of America, 105(50), 20021-20026. NATL ACAD SCIENCES
- Publication Year :
- 2008
-
Abstract
- The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRT mRID ) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT mRID mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRT mRID mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT mRID -derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.
- Subjects :
- TR
Peroxisome proliferator-activated receptor
glucose regulation
PPAR
Mice
Homeostasis
Gene Knock-In Techniques
Nuclear receptor co-repressor 2
chemistry.chemical_classification
COACTIVATOR
Multidisciplinary
ADAPTIVE THERMOGENESIS
Thyroid Hormone Receptors beta
corepressor
Biological Sciences
ADIPOCYTES
DNA-Binding Proteins
Thyroid hormone receptor alpha
Hormone receptor
COMPLEXES
PPAR-GAMMA
ENERGY-BALANCE
Thyroid Hormone Receptors alpha
medicine.medical_specialty
Chromatin Immunoprecipitation
Thyroid Hormones
Down-Regulation
Biology
adipogenesis
Thyroid hormone receptor beta
Internal medicine
medicine
COFACTOR
Animals
TRANSCRIPTIONAL COREPRESSOR RIP140
Nuclear Receptor Co-Repressor 2
HORMONE-RECEPTORS
Transcription factor
Thyroid hormone receptor
OXIDATIVE-METABOLISM
Mice, Mutant Strains
Protein Structure, Tertiary
PPAR gamma
Repressor Proteins
Endocrinology
Glucose
Nuclear receptor
chemistry
Gene Expression Regulation
Genes, Lethal
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 105
- Issue :
- 50
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Science of the United States of America
- Accession number :
- edsair.doi.dedup.....cd0cea165f9ca2877e4e647237b7d400